Title: Discovery of microRNA regulatory modules controlling human pancreatic islet function The goal of this research project is to characterize comprehensively the role of microRNAs (miRNAs) in human pancreatic islet function. Islet cells are responsible for the metabolic response to changes in blood glucose levels. Progressive dysfunction of the islet underlies type 2 diabetes, a chronic condition characterized by hyperglycemia, which can lead to substantial morbidity including kidney failure. The gene regulatory networks (GRNs) that drive islet biology are largely uncharacterized. miRNAs are post- transcriptional regulators and critical components of GRNs. Recent studies have implicated miRNAs in islet function. Comprehensive analysis of miRNA expression and activity in primary human islets will significantly increase our knowledge of the GRNs that underlie islet biology. Therefore, this project will use high-throughput genomic approaches to systematically characterize all miRNAs in resting and glucose-stimulated primary human islets (Aim 1), and identify the regulatory modules that influence their differential expression patterns (Aim 2) and targeting activity (Aim 3). These aims will contribute significantly toward mapping islet GRNs, which will facilitate the identification of clinically relevant pharmacological targets for addressing islet pathophysiology in diabetes.